Despite the proliferation of therapies, congestive heart failure (HF) remains a progressive disease. There is therefore a desperate need for innovative rather than incremental therapies to reverse the course of ventricular dysfunction. Recent advances in understanding the molecular basis of myocardial dysfunction, together with the evolution of increasingly efficient gene transfer technology, have placed HF within reach of gene-based therapies. One of the key cellular alterations in both human and experimental HF is a defect in sarcoplasmic reticulum (SR) function, which is responsible for the abnormal intracellular Ca2+ handling observed in failing cardiomyocytes1-4 Deficient SR Ca2+ uptake during relaxation has been identified in failing hearts from both humans and animal models and has been associated with a decrease in the activity of the SR Ca2+-ATPase (SERCA2a), which is at least partially due to enhanced phospholamban (PLN) inhibition. Restoring SERCA2a levels or reducing PLN inhibition has been shown to improve function, metabolism and/or survival in a number of experimental models of heart failure. Over the last ten years, we have initiated and recently completed a first-in-man phase 1 clinical trial of gene therapy for heart failure using adeno-associated type 1 (AAV) vector carrying SERCA 2a5. The safety profile of AAV gene therapy along with the positive biological signals obtained from this phase 1 trial has led to the initiation of a phase 2 trial of AAV1.SERCA2a in NYHA class III/IV patients6. More recently, we have shown that by constitutively activating the inhibitor of protein phosphatase 1 (l-1) within the failing heart, there is improvement of SR Ca2+-handling, contractility and, most importantly, reversal of adverse remodeling by directly decreasing fibrosis and cardiac hypertrophy7-13. Even though AAV vectors have been proven to be safe in multiple trials including in patients with heart failure, their use for gene delivery has the following limitations: 1) they are not specific for the heart and 2) antecedent neutralizing antibodies to any individual serotype account for 40% of these patients which would need to be excluded from clinical trials14-17. We have therefore developed a cardiotropic chimeric of AAV that targets more specifically the heart and escapes the inherent immunity in patients. We, therefore, propose to take advantage of these novel chimeric vectors, which are also known as Bio Nano Particles (BNP), to directly target I-1 in experimental models of heart failure14-17. Within STAGE 1 of this proposal we will validate the target using this novel vector in a pre-clinical model of heart failure. In addition, we will analyze the prevalence of pre-existing neutralizing antibodies against our new cardiotropic vector in a heart failure patient population. In STAGE 2, we will carry out a phase 1, Open- Labeled, Dose-Escalation Trial of BNP111.sc-CMV.l1c by Intra-Coronary Infusion in Patients with Heart Failure followed by a A Phase 2, Randomized, Double-Blinded, Placebo-Controlled Dose Escalation Trial of Intra-Coronary Infusion of BNP111.sc-CMV.l1c in patients with heart failure. RELEVANCE (See instructions): Heart failure is a major cause of morbidity and mortality in the United States despite the novel therapies that are used to treat these patients. Gene therapy has emerged as a novel and viable strategy to target specific abnormalities in the failing heart. We have developed a cardiotropic Adeno-Associated Vector (AAV) that specifically targets the heart and escapes the inherent immunity in patients. This new cardiotropic vector combined with a novel well validated target offers a new strategy for the treatment of heart failure.